The members of the genus Ochrobactrum are included in the alpha-2 subgroup of the domain Proteobacteria. They are primarily soil dwellers known to be pathogenic only in critically ill or immunocompromised patients or in patients with indwelling catheters. Although in such situations Ochrobactrum can cause meningitis, osteomyelitis, bacteraemia, and septicaemia, these bacteria are unable to establish chronic infections by themselves and are cleared from normal hosts after catheter removal (Cieslak, T. J., C. J. Drabick, and M. L. Robb. 1996. Pyogenic infections due to Ochrobactrum anthropi. Clin. Infect. Dis. 22:845-847.)
Since the composition of all lip polysaccharides, main component of outer membrane of gram-negative bacteria follows a general principle, which includes a polysaccharide attached to a lipid component termed lipid A through a specific sugar called 2-keto-3-deoxyoctulosonic acid (KDO) (Rietschel, E. T., Schade, U., Jensen, M., Wollenweber, H. W., Luderitz, O. and Greisman, S. G. 1982. Bacterial endotoxins:chemical structure, biological activity and role in septicaemia. Scand. J. Infect. Dis. Suppl. 3:8), it has been assumed that all LPS molecules have identical biological effects.
However, this concept has been modified by studies showing great variance in the capacity of several LPS species to produce cytokine synthesis, this effect being related to the structural features of their lipid A portion (Netea, M. G., van Deuren, M., Kullberg, B. J., Cavaillon, J. M. and van der Meer, J. W. M. 2002. Does the shape of lipid A determine the interaction of LPS with Toll-like receptors? Trends Immunol. 23:135.).
Legionella pneumophila, a Gram-negative facultative intracellular bacteria, is also similar to Brucella as regards both low endotoxicity and chemical structure of its LPS and significantly lower than that elicited by enterobacterial LPS (Zahringer, U., Knirel, Y. A., Lindner, B., Helbig, J. H., Sonesson, A., Marre, R. and Rietschel, E. T. 1995. The lipopolysaccharide of Legionella pneumophila serogroup 1 (strain Philadelphia 1): chemical structure and biological significance. Prog. Clin. Biol. Res. 392:113. 26).
Ochrobactrum anthropi is the closest known relative of brucellae (Velasco et al. International Journal of Systematic Bacteriology 48 (1998) 759-768). Despite their close phylogenetic relatedness, B. abortus and Ochrobactrum differ markedly in OM properties and that these wide differences are caused at least in part by little changes in the LPS (Velasco et al. Infection and Immunity 68 (2000) 3210-3218)
The complete core-lipid A backbone of the LPS from Ochrobactrum intermedium LMG 3301 and the O-chain from Ochrobactrum anthropi LMG 3331 LPS was determined (Velasco et al. Carbohydrates Research 306 (1996) 123-126; Velasco et al. Carbohydrates Research 306 (1998) 283-290; Velasco et al. Infection and Immunity 68 (2000) 3210-3218).
The strain of Ochrobactrum intermedium LMG 3306 was described by Velasco et al. (International Journal of Systematic Bacteriology 48 (1998) 759-768) and nevertheless, no LPS from Ochrobactrum intermedium LMG 3306 have been described previously.
On the other hand, Approximately 900,000 cases of sepsis occur annually only in the United States, causing roughly 210,000 deaths and costing almost 17 billion dollar. Sepsis is a common disease with rising incidence and a mortality ranging from 27-48%. Septic shock is a consequence, frequently lethal of sepsis. The overwhelming inflammation that occurs along with infection during sepsis has been the target of several therapeutic interventions. Despite, the inflammatory aspects of sepsis more that 20 years of clinical trials with general anti-inflammatory agents have shown that this approach was not overly successful.
The pathological mechanisms leading to sepsis are complex and far from being understood. Sepsis involves a systemic inflammatory response followed by a compensatory anti-inflammatory response. The balance between them is crucial for host survive. Moreover, animal models of sepsis do not easily mimic this complex nature of sepsis in human patients.
Recently, there have been some attempts to treat those effects by Toll-like receptor (TLR) antagonists since it is believed that most of the consequences of the septic shock are due to huge release of circulating endotoxin (LPS). Thus, Eritoran, a structural analogue of lipid A portion of LPS which acts as TLR4 antagonist is in phase II and showed a reduction in mortality in severe sepsis patients In addition, TAK-242 is a TLR4 signal transduction inhibitor that decrease proinflammatory cytokine levels and also decrease mortality in a subgroup of severe sepsis patients with high IL-6 levels.
Nowadays, there are many infections diseases for which there is no vaccine available. In some of these cases the failure is due to the lack of the correct adjuvant to induce the correct and appropriate immune response—For some infections agents, as intracellular bacteria, viruses and most protozoans, the protective immune response is of the T helper 1 type (TH1) characterized by IFN-gamma production. In contrast, protective response against most helminths is of the type 2 (TH2), characterized by IL-4 production (Fresno, M., M. Kopf, and L. Rivas. 1997. Cytokines and infectious diseases. Immunol Today 18:56-58). Few adjuvants, are available for human vaccines formulation, due to the toxicity of many of them, due to an exarcebated Th1 induction. Alum, which is really not an adjuvant, is used in most human vaccine formulations. Recently, agonist of Toll-like receptors (TLR) have attracted great interest (Hoffman, Nature Reviews Drug Discovery 4, 879, 2005) (Kwissa; Expert Vaccine Rev., 6, G73, 2007). Several antigens together with several agonists of various TLRs are currently being analyzed.
Finally, one of the major problems of any vaccine formulation, including those already licensed in that they rarely works in immunosuppresed subjects. Besides some of them have secondary effects on those patients (Kwissa, et al 2007).
The complete core-lipid A backbone of the wild deep-rough LPS (a LPS in which O-Chain is not present and lack some monosaccharides from the outer core part) from Ochrobactrum intermedium LMG 3301 was described by Velasco et al. Carbohydrates Research 306 (1998) 283-290; the O-chain from wild smooth LPS from Ochrobactrum anthropi LMG 3331 LPS was determined (Velasco et al. Carbohydrates Research 306 (1996) 123-126; and lipid A, and molecular weight of the complete LPS was published by Velasco et al. Infection and Immunity 68 (2000) 3210-3218.
The strain of Ochrobactrum intermedium LMG 3306 was described by Velasco et al. (International Journal of Systematic Bacteriology 48 (1998) 759-768) and nevertheless, no wild smooth LPS from Ochrobactrum intermedium LMG 3306 have been described previously.